Stanford University I would like to get started please so my name is Patrick house I am a neuroscience PhD student I work with Robert and Roberts lab on the first year and I study something that you guys will eventually hear about but I don't want to ruin the punchline but today we're going to talk about memory and plasticity and so to two days ago on Wednesday right you guys also add in here in this room and you learned some of you for the first time some of you for maybe the the tenth time the basics of neurobiology of how a neuron works how neurons you have a presynaptic cell you have a postsynaptic cell and this kind of simplified version of the communication and information transfer and something interesting happened between now and then which is that now you sit in the same room and something about you knows something about neuroscience now right you heard one of the TAS talk you slept on it and then you come back now and you have assimilated integrated into your identity into what you know new facts and this lecture is about how you do that and to kind of get at what memory is we need to think about a lot of different ways in which it's interesting and a lot of different kind of spectrums and and severity 'z about memory right so why is it that some memories last our entire lives whereas other memories we hear and they're fleeting they go away in a second why is it that someone who someone sitting next to you in bed telling you a story and as you go to sleep you can't remember it as you wake up you can't remember your dreams but if that exact same person that exact same story was told to you as they were sitting next to you in a car and you get into a car accident suddenly that memory becomes salient you may remember it for years if not your entire life and you may actually associate either the story itself the voice of the person with that traumatic event and you might get post-traumatic stress disorder so if the mechanism is the same between these two types of memory between ones that are flee and forgetful and ones that last your entire life the question is how does environment how does context fit into shaping these types of memories and so to order in order to understand that we have to kind of get at what are the mechanisms of memory and how are these contextually motivated so I want introduce to you first Stephen Wiltshire who is an architect if not in practiced at least in in mind he is an autistic savant and he has been mute since age three and he has this remarkable capacity which I'm actually going to test you guys on slightly here if you have any kind of inclination to sketch or you happen to have some sketch paper with you I want you to this will take approximately 60 seconds to span across all of Rome draw it from memory in your 60 seconds because Stephen Wiltshire has this amazing capacity to take helicopter rides he's done this over Tokyo he's done this over New York he's done this over Rome and over London and in 20 minutes he can then sit down and recreate every single building every single column every single window in correct proportions from the correct angle in which the helicopter ride what and so you may be thinking okay your 60 seconds are almost up can you guys do it you may be thinking okay if any of you are artists out there you may be thinking this is unfair why can't I do this and as neuroscientists our first thought is okay this is unfair why can't I do this and but really it can tell us something interesting about memory right so so you come at it with two questions first question before and after this helicopter ride what is different in Stephens brain and second on this theme of individual variation that that we keep kind of harping on in class why is it that he can do this and we can't do this and these are two important questions that if we could answer those questions we would know a lot about what memory is and so it really makes sense to kind of go back to what it is that we know so far about neurons the basics of one neuron and how it is activated right and so we have a presynaptic cell and we have a postsynaptic cell and in our simplified version we can kind of know now and what I'm going to tell you is that memory learning happens to the best of our knowledge in the synapse in the place between the space between the pre and the postsynaptic cell but to understand why it is that we think that we kind of need to go back about a hundred years to when when people scientist neuroscientists were investigating the brain investigating memory and they thought that the smallest unit of the brain that they knew was the neuron so because of our kind of tendency to explain what we don't know in terms of the smallest unit of thing that we do know they thought okay this makes sense right a memory is a new neural and when you learn a new fact when you learn the basics of neuroscience you are growing new neurons and each individual fact is associated with one new neural for instance they may have thought that okay you guys learned on Wednesday that the axon hillock is the you know site of the generation of the accident but action potential so then that is a new fact and then a new neuron would then be formed and okay so that actually might not make I just realized that that actually might not make sense because at the time that they thought that they didn't know what an excellent eye look is so maybe that formulation doesn't even make sense but the idea is that a couple decades later people discovered the synapse they discovered that neurons were not just one interconnected thing that there is space there's a gap between them and as soon as they discovered the synapse that then became the smallest bit of information we knew about the brain and then theories came out saying okay well no memory must be the formation of synapses so the dogma at the time was then that okay new fact axon hillock what does this mean in the brain you can see this in the brain this is takes the shape of a new synapse being formed and what we think of now is that well this isn't exactly right because new synapses are not being formed all the time and new neurons are not formed in the adult brain which isn't entirely true but we'll get back to that but the idea is just that memory and storage of kind of learning what I'm going to tell you is that it's in the synapse and that it involves modulation and change of the synapse and why do we think that because we understand the molecules and we understand at a molecular level what's happening in the synapse when it changes and so that is thus now our smallest level of understanding of the brain and so of course we think oh well that's probably where memories so that's the dogma that we're going to start with and we're going to start with this idea that memory is synaptic plasticity memory is when the space between the presynaptic and postsynaptic neuron changes in some way and not only that it changes in one direction it gets stronger it's strengthened and so what this means is that if you have your presynaptic neuron and you fire it and you get some amount of response that over time if you give enough kind of presynaptic activation in a certain time window that you will then get a heightened strengthened response in your postsynaptic cell eventually and that is the kind of mechanism the overarching broad mechanism of LTP and so what we need to do to understand memory is to focus on the synapse so what we get is our kind of classical picture which is that you have your synapse and a neurotransmitter is coming out and that neurotransmitter is excitatory and in your postsynaptic cell what you're getting is you're getting a small amount of activation you're getting current that comes into that cell you're getting ions some sort of some sort of response for any individual piece of neurotransmitter and so what this is is a version a simplified version of what is called heavy and the city and so there's this guy head you have to know there's a few kind of names you have to know in neuroscience and he's one of them and he came up with this idea the kind of only bumper sticker that neuroscientists ever have on their car which is that neurons that fire together wire together and what this is saying is that you have your standard picture of a very very simplified version of a presynaptic cell that's releasing an excitatory neurotransmitter and that when it does so you get a response in your postsynaptic cell and so the if you will remember from kind of to one lecture ago that that excitatory neurotransmitter is glutamate and kind of though if you're going to spend any time and energy into remembering one neurotransmitter that might be relevant for the class this is the one you want to remember you don't have to remember it right so mostly the idea is just that it's excitatory and why is this important because information is transferred in the brain through activation and in order to transfer information you need excitatory neurotransmitters you need your neurons to be activated but as we know kind of from what I've told you so far that repetition is what drives memory I would suggest that you remember that glutamate is the excitatory and one and only neurotransmitter that you have to know that say there's a test question that says what is the one excitatory neurotransmitter in the brain that you have to know you would respond glutamate and then you would be right and so you can imagine that for this type of simplified diagram if we were to strengthen the synapse if we were to get some sort of plasticity some sort of change potentiation what you you could you could think of a few ways of doing this right you could take the presynaptic neuron and change how much excitatory neurotransmitter is released you could change how much glutamate is released and presumably if you release more of the little circles with you know positive charge in them then you're going to get more activation in the postsynaptic cell another thing you could do is write basic kind of neuro chemistry and this in this diagram is that each of those neurotransmitters is binding to a receptor on the post to excel and so what you can do is take that individual receptor and you can make it respond more to a single individual unit quanta of neurotransmitter alternately you could just increase the number of postsynaptic receptors on yourself and all of these would be mechanisms by which you could take this very very simple synapse and potentiate it such that you get the same release you get the same neurotransmitter and what you get is subtle because LTP is often very subtle you just notice that the response is slightly large right slightly larger response given the same amount of input given the same amount of output of the presynaptic cell and this is the entire idea of LTP long term potentiation this idea that at your individual synapse you can potentiate it you can change it it is plastic but there should be one large red flag here right which is okay you one of one of these kind of caveats is well your presynaptic neuron how does it know whether or not LTP should be undergone how does it know whether or not LTP has been induced this requires a kind of communication between both the pre and the post synaptic cell right that how would the presynaptic cell which is already released as neurotransmitter know and what you get is this this kind of heretical type of neurotransmitter that can actually we call it a retrograde neurotransmitter that can actually be sent back from the postsynaptic cell and it's a gas nitric oxide is an example of one it's what you get in your your dentist and it kind of goes back and diffuses back across the synapse and actually modulates how much neurotransmitter gets released from the presynaptic cell so we have these mechanisms right we have these mechanisms of LTP and the question then is where does this happen in the brain and and why is it that we believe that these are the places of LTP and one of the kind of things you need to know this is our first kind of dive into is you need to know that hippocampus right it was introduced to you last lecture but if there's one neurotransmitter you need to know its glutamate and if there's one kind of neural anatomical structure you need to know at this point it's type of campus and so how I'm kind of always jealous of these kind of these autistic savants they can memorize 10,000 digits of pi and you know take a helicopter ride and then fully recreate this kind of cityscape of any city they see and if you read interviews about how they do it it's really interesting so what they what they seem to do is not memorize such a sheet of a bunch of digits string of 10,000 digits of pi they'll take a walk through their childhood town and they'll say that they put one of the digits on each and every object right so your mailbox will be the first digit and then your neighbor's door will be another and then their window will be a three and then they are not kind of re conceiving and reconstructing just a sheet of boring numbers they're taking kind of spatial tours through their memory and what this always kind of compels me to do is make these kind of visual mnemonics right so I'm going to give you a visual mnemonic for the one way you have to remember that the hippocampus is the site of memory and the site of LTP insofar as this class is concerned which is okay hippo horse right we have we learned that last time it looks kind of like a seahorse but that doesn't really make sense what if you think about this whatever you think about the Hippodrome right back in Rome Hippodrome was the the circular arena where you had your little chariot races right because of horse horse and III there's two different scenarios that I want you to imagine the first is you guys remember a Michael Jordan and Larry Bird they have this commercial where they played horse right and what they were doing is they're playing you know you have to make a basketball shot and then the next one you have to remember what that first-person date exactly and you have to recreate it right so what I like to imagine is Larry Bird and Michael Jordan playing a game of horse in the Hippodrome back in Rome and then you can kind of get this idea of how memory is related to hippocampus and this horse structure and if that doesn't work for you I have one more which is actually my favorite which is you can imagine the the entire amphitheater the entire Hippodrome filled with people and there's that one there's that one Emperor who named his horses senator do you guys know who that is what's his name I don't know his name Caligula there we go okay so imagine the entire Hippodrome is filled with people and Caligula is there and he gets his senator horse in the middle of the field and the horses sitting kind of crossed leg and he's typing out your memoirs okay on a typewriter and that is how you're going to remember that the hippocampus the Hippodrome the horse is where memory is formed okay so now you guys are all you guys are all autistic savants now so really though what we need to determine is okay why is it that we really think that the hippocampus is the site of LTP and memory formation it turns out that there is actually adult neurogenesis and adult plasticity right so in the last 10 years we've discovered that the adult brain really does actually form new neurons and for the last hundred years we kind of disregarded that and said those guys who initially believed that every new neuron is associated with every new fact those guys were just totally wrong and ridiculous what a ridiculous concept and so perhaps eventually in the future we will have to incorporate this idea that there does seem to be some neurogenesis in the brain but much like how we learned that there is non genetic kind of inherited traits right which we had learned from kind of the disreputable Lamarck way back in Lamarckian evolution that there is no for a hundred years we thought no it's impossible there is no non-genetic inheritance of traits but it turns out that well okay we do seem to have some kind of non-genetic inheritance and so Lamarck isn't entirely wrong and it turns out this is a kind of similar thing where the people of most disrepute are often just a little bit wrecked so probably people that used to think that adult neurogenesis has something to do with memory are probably a little bit right but we're going to stick with the canon which is that LTP happens and that it happens not on the level of the neuron not on the level of the synapse but on the level of the plasticity of the synapse and so why do we think it's ap campus we kind of get at it from a few ways the first way is that hm this kind of well dressed epileptic who had his hippocampi removed right and what happened was he had selective removal of just his hippocampus and he could no longer remember anything I don't you could not form new memories whatsoever so with with these types of conclusions in addition to evidence that if you watch and record from neurons in the hippocampus as you're giving someone a learning task then you see LTP if you pharmacologically block LTP you see changes in the hippocampus and so all these pieces of evidence are trying to get at the idea that the hippocampus is necessary for kind of memory and memory consolidation but if you introspect a little bit you can probably realize that well we undergo all kinds of forms of learning and memory right we have motor learning we learn how to shoot baskets we learn how to throw darts we understand kind of emotionally that events that are more emotionally salient are more memorable and so how is it that these types of things are also encoded in our brain also encoded in the same region the one region the hippocampus and what that turns out to be is that well it's not just that one region LTP is happening all over the brain that if you look in your emotional and regulation centers if you look in your emotional court cortices you also see LTP and this makes sense because these types of memories have to have different methods of storage and retrieval and also that you can imagine this type of excitation this type of synaptic plasticity can go wrong right in post-traumatic stress disorder for instance you get LTP and you get LTP is severe and you get severe LTP potentiation of your synapses in those emotion regulation centers that create a situation where the context leads to memories that shouldn't necessarily be brought up that shouldn't necessarily be retrieved and so we see this mechanism for types of behavior that we know types of things like why memories last certain memories certain emotionally salient memories last for a long time and others don't and we can also imagine that this is a physiological process and that it can go wrong occasionally right we all know that memories are degraded sometimes intentionally so sometimes unintentionally so that there are certain things we want to remember despite any and all repetition about glutamate being the excitatory transmitter we just don't remember them and there are some that just kind of fade away into time into the into the oceans and but what is happening is that there are mechanisms for intentional disruption of LTP and you can think of a few so hypoglycemic states if you are really really hungry you get insulin kind of Cascades that end up reducing LTP if you're starving it's not a good time to try to remember things it's a good time to try to go out and expend energy finding food as we'll learn later in lectures there are some some stress hormones and these stress hormones actually give us in a selective memory advantage in the short-term right if you're in a car crash you remember the slow motion details of the entire event and this has to do with these stress hormones these fear hormones coming out and saying okay well we want to be able to remember this moment so we can learn from it next time if we survive but if you do this chronically if you do this for a long time window throughout the lifetime of the organism then you can actually get damage to LTP and damage to memory so it's about time window it's about these same mechanisms that can enhance memory can also be deleterious eventually so and another kind of probably more familiar one perhaps not to the introverts but perhaps to the extroverts in the crowd is that if this lecture were on Saturday morning I could probably ask you guys what you did last night and some of you would not be able to tell me with with delicate accuracy what happened on Friday and you might not be able to tell me the story that was read to it you know bedtime or even who read you the story at bedtime and this is because ethanol alcohol right directly disrupts LTP and we see this and we see this in the hippocampus and these are the types of things behaviors that we know of right we know that emotionally salient memories last longer we know that alcohol somewhat there are differential effects of types of substances on memory we know that it's hard to remember things right before we go to sleep and so what's interesting is can we get at a physiology that explains all of these things and so I'm going to give you 60 more seconds there's going to be a pop quiz at the end by the way you have 60 more seconds to do this and what is interesting here is that when we get these met when we get down to these kind of physiological mechanisms and we have two ends of the spectrum we have HM and we have Stephen Wiltshire right someone who cannot form any memories whatsoever and then someone who can do this in a 20 minute helicopter ride recreate the entire landscape and the question is the theme of this class is often one of individual variation how is it that one person can not be able to form any memories whatsoever how is it that one person can have an autistic kind of photographic memory and where do we fit where do people where does memory fit in a properly functioning way and like most of the kind of spectrums that are introduced into this class right one of imprinted genes tournament versus pair bonding species things like that the answer turns out to be we are somewhere in the middle between hm no hippocampi no formation of new memories and Stephen Wiltshire so one more thing kind of we need to discuss with the theme of this class is that often we'll give you a lecture and then maybe the next lecture maybe kind of five minutes later we'll tell you it's all wrong or we'll say no you've been waiting my Opik that's not how you should see these things and what we need to do in order to understand somewhat about the context of memories is to take and expand your my Opik view of this simplified version of a neuron right so far we've gone into what a single neuron functioning looks like and we've gone into what a single neuron as it transmits a signal to another neuron looks like how there's a gap in between the pre and the post synaptic cell and what that information transfer looks like and how we can change that information transfer how we can make it plastic but there's a problem here which is that if we're trying to learn anything about the brain we have to understand that the brain is really complicated and that there's a hundred billion neurons and that sometimes these individual neurons will connect to 10,000 other neurons and sometimes each of those 10,000 neurons will have 10,000 neurons that connected to it and so the question the kind of first I don't know as a neuroscientist what I look at that the first thing I do is want to give up right and I do and then the second question the second kind of thought is okay maybe it's time to expand the simplified version of the neuron that we have it's not just one neuron talking to another neuron it's not just a single synapse but that it's the dynamics of many many interacting neurons and that kind of as these dynamics expand as these dynamics get introduced into 10,000 neurons at the same time 10,000 dendrites dendritic arbors connecting to 10,000 other like axonal processes then we see that things that didn't matter so much in the single individual neuron actually mattered quite a bit when you're talking about a hundred billion neurons right so one of the things to introduce here is the concept of noise into the individual signal transfer into the individual information transfer a neuron as we presented it was something that fires an action potential transmits information every single action potential leads to neurotransmitter release which leads to postsynaptic kind of response but these are very delicate things right the an individual neuron is constantly in flux with how much current is coming in and out ions are flowing around it's not as simple as a static neuron that then gets activated and then passes on a message to another static neuron which then gets activated what you get is often a lot of times you'll get random and spontaneous generation of signal of action potentials and sometimes of current in the postsynaptic cell and one of the major tasks of the brain is figuring out figuring out what is signal what is appropriate and end meaningful signal versus what is this noise if you can imagine on a single neural level the noise might not have that much impact but if you're talking about 10 100 billion neurons you're going to get noise all over the place that will just kind of lead to this new static of noise that you don't know what to make of the world anymore you don't know what to make of the signal you don't know what to make of individual neural signals and so what we need to do is to start considering neurons in terms of how they interact in dynamics of groups and one of the first ways and the most important ways to think about this is to understand that neurons are not just excitatory forces that that information yes is generated by kind of glutamate and the transfer of excitation but that neurons have a capability to inhibit right and one of the important ways that they differentiate signal from noise one of the important ways to learn what is noise and what is not is to inhibit and I'll explain how it is exactly that the inhibition works but one of the first oh that's pretty high one of the first ones to understand is that a neuron can inhibit itself right which is not really it seems like it could initially be some sort of masochism but it's really not it's just that the neuron is trying to sharpen the signal that it's sending right so neuron is firing and firing over and over and over and what it wants to say what it wants to be able to do is accurately give a precise description of the signal of the information and what it can do is inhibit itself to say I'm done no more spontaneous noise no more spontaneous little little bits of current I am done with my signal and what this is is it allows for temporal sharpening it allows for the ability of a neuron to say this was my signal it was meaningful I really meant it you know and and inhibit the kinds of random noise and spontaneous things that could happen another aspect type of inhibition that's very important to separate noise from not noise is spatial inhibition so what this is is your individual neuron not only can it send kind of processes and inhibit itself it can actually send processes out and inhibit its neighbors and how might this be kind of useful and important is that it's it can say essentially okay this signal is real the signal is the signal that I want to send the information that I want to transfer and not only that ignore my neighbors it's really me it and what this allows you to do is get spatial sharpening so what this allows you to do is say in the kind of field of things that you're trying to perceive a certain neuron will respond to a certain section of that field correct and what this is saying is I am activated and in and you kind of inhibit your neighbors so that you're more sure that your signal is true and how can we relate this what is how can we make sense of this there's a very simple type of feedback network that that should kind of elaborate this idea which is pain and pain sensation and so we all probably at some point our lives presumably have discovered and felt pain and there's kind of two general qualities of pain you can have really really fast sharp pain and you can have this dull aching throbbing and what people found when they investigate into your spinal cord and into kind of your sensory peripheral processes is how this pain is generated and it's generated on two separate types of neurons and one carries fast pain one carries the sharp fast stuff one carries the slow dull stuff and what you find is that these are kind of intertwined in this delicate feedback loop such that the fast spiking first pain will generate kind of eventually the slow-moving pain it will fire the other neurons next to it the neighbors and say okay also start this kind of slow pain spike but then the sec the slow pain spike can come back and inhibit the first kind of sharp spike such that it stops right we're trying to get information about the world and your body is trying to do what it can with that information and if you get stung by something you want really sharp pain to be like hey pay attention to that make sure it's not a scorpion that's still there but you don't need the sharp pain forever you want to be able to inhibit it and just say okay pay attention but then you know just to make sure you don't walk on it anymore and get it infected we're going to make it hurt a little bit and so this is your body trying to make the most of this type of information and what it's doing is using lateral inhibition in this complicated way actually simple way to allow for these two types of two types of kind of transmissions of information that was a very simple example and I think there's a much more complex example when we go into the types of complex kind of visual stimuli that vision gives us right and you can imagine that lateral inhibition the same type of spatial sharpening of a signal can come into play as we're trying to figure out and piece together the visual world so what this is doing what this kind of lateral inhibition allows for is it allows for visual neurons to receive input and then to say it is me right this is the signal that I want to send not only that inhibit the neighbors and what this leads to is this emergent property of these kind of retinal cells that allow for specific types of signal and allow for specific types of receptive fields so in your eyes your kind of neurons in the back of your eyes if you just stand still they only have a certain angle of light that they can get and that idea is this idea of receptive fields that they are responsible for that field and they're responsible for saying if there's a signal there this is what it is and this is how it's relevant and what this type of lateral inhibition allows you to do is it allows you to say okay I write your your neuron gets a signal and it wants to say okay that's an edge an edge detection contrast detection if you look around in the objects in the room often you can you define them by their edges so we have this elaborated and of neural mechanism involving inhibition and excitation that allows for this type of contrast enhancement and what can we do with this kind of even even more right so these guys Hubel and Wiesel decided that they were going to look okay another brief anecdote so there's this commercial when I was young and it was Michelin tires right and if any of you guys ever become kind of marketing people which there's enough of you that statistically someone will I don't know why you don't make commercials that are scary because this commercial frightened me and I was like six and I remember it to this day so why not if you want someone to remember your product just make it like take what you know from this and use it to manipulate people that's what education gives and so I remember this commercial and I just remember it was four Michelin tires and their whole point was that no matter how fancy your car is no matter how much you spend on your car there's only four points of contact between you and the road right and it's on your tires and I don't know why but this blew my mind and it scared me and it made me okay recognize that yeah you should get good tires so cubile and ezel they took essentially same wad right which is that okay we have this complicated visual world and we know that we've put it together somehow but our only access to this information is through the retina right we have okay the light is the road these are our two tires right we only have two tires to connect with the road and so what they they're logic was that if we look at each individual neuron in the retina we and trace it back we should be able to see somehow how this visual world is constructed how it is that we go from the only signal the only signal from the outside world we get to this complicated visual field and what they what they found was that if you look at the neurons in the back of a retina and then look at kind of where they get where they synapse back in kind of your visual cortex they found a one-to-one correspondence that if you activate a certain neuron in your retina you'll get a kind of spatio topic which means they're oriented in the same way and all the neurons are aligned in the similar way field in the back of your visual cortex and v1 and so what that essentially means is that kind of your eyes are smushed to the back your head right there's no information that necessarily gets enhanced or reduced between your retina and the back of your visual field and they're like okay great and so these guys Hubel and Wiesel they won the Nobel Prize if you could win more than one they probably would have won four by now they're these Harvard neuroscientist back back in the day and they are pretty much the kind of who you need to know right you need to know Hebb you need to understand glutamate you need to understand LTP and Hubel and Wiesel if you're going to be a neuroscientist be interested in the brain they will come up and you have to in you know if you're neuroscience you have to invite them to your wedding and you have to have you have to do everything right I don't even know if they're they might even be dead you have to say on stem or something but what they decided to do is then okay now we're at v1 we're at the one level of visual cortex how can we what else can we do where does the where does the scene get constructed that we see and what they did was looked one layer up and they did the exact same thing they fire an individual retinal neurons and they looked in the next layer up and absolutely nothing happened there's no activity anywhere no matter what they did it fired all of them there's no activity and they were like oh dammit we're not going to get invited to any weddings and how what are we going to do and but what they discovered was that if you kind of activated enough retinal neurons and that they were in a certain spatial orientation say a line then you get activation in this other layer of your visual cortex and what they discovered and what was on I'm sure the construction of all of their wedding invitations was that if you have you have certain neurons that are selective to certain orientations of lines like so if you imagine these are four neurons a single neuron will be responsive to a vertical line a single neuron another one a different one will be responsive to a 45-degree angle right a horizontal line 135 degrees and so what you get and you're starting to piece together is this is this way of constructing the visual world that is layered and that extracts out features and that through those features you get kind of individual neural activation and you might imagine that if you go up even further you would get some sort of more higher-order types of activation individual activation in your visual cortex something like say a neuron that only responds to an orange or a neuron that only responds to a banana or a neuron that so this is one of the the terms in the field only responds to your grandmother right and they call it a grandmother neuron and there was kind of eldorado type quest for grandmother neurons right where can we find it and the problem is nobody ever found it and so then the question becomes again related to memory related to even our understanding of these kind of networks of neurons where are these memories stored and so - well this is slightly out of order but basically this is an example of again your lateral inhibition right so to understand how it is that these kind of signals are sharpened right this is a nice visual illusion do you guys see little dots of dark between each of those that is not as an artifact right that is an artifact of your visual perception that is an artifact of you constructing that and why is that happening because at each of those individual corners you're getting the most amount because of the four kind of axial bars of white of lateral inhibition so in every single one of your brains right now and whenever you look at the you know individual corner you're getting lateral inhibition and so you can imagine that this type of thing is it is a demonstration of lateral inhibition another type of thing when I was talking about pain right so there's this fascinating thing where we all know this where if something itches so you have mosquito bite and you want to scratch the hell out of it because sometimes it feels really good you notice also that you can stretch around it right you can make hard kind of painful stimuli in the immediate vicinity and just do it really really hard enough and you you get lessening of pain and what that is is the same type of thing it's lateral inhibition of the focal point of the mosquito bite and so these things sound abstract but these things really are real and we can see them and we can feel them if we know where to look so one last idea right we're trying to get at okay where are these memories store where are these facts where is what you know now about neurobiology stored and we kind of it's helpful to introduce the idea of neural networks right there's 100 billion neurons in the brain these are not communicating one-to-one these are communicating with dozens tens of thousands of other types of neurons and if you simplify this down to just the basic idea of a neural network such that you have you're kind of bottom first layer cells and these first layer cells respond to respectively left to right right Monay stays on they got they just respond for some reason they have they have undergone LTP that is what they respond to in this very one-to-one Hubel and Wiesel kind of way but what we noticed is that there's this elaborate property you get when you start to combine neurons with many many other types of neurons which is that you get a network and you get a network without one-to-one correspondence so if you look at the top row and you get neurons a through e a still responds in this one-to-one way with just Monet right E again you got just dig up so those are not really informative in the way in which we want to understand the emergent property and what's important about neural networks what we get out of neural networks is kind of emphasized when we focus on C right neuron C doesn't know if it gets activated what can you tell you don't know which kind of input they came from you don't know whether it came from the first layer neuron one first layer on two or three you don't know whether or not it was a Monet Cezanne or daga all you know is that it's one of those three and what you get now is this idea that you can have concepts and you can have categories and you can have a category of Impressionism that doesn't necessarily give you information about individual types or names or which narnun came from but you have a network of neurons with different concepts in it and amidst this network you can now understand how it is that environment and context can impinge on the storage and retrieval effects right so the the idea that emotionally salient memories are are kind of longer lived in your brain in your synapses in your kind of plasticity than other ones well how is that true if they're not contextually related if the mechanism is the same everywhere but what you begin to see is that if you combine context in this this version of neural networks you start to get the neural representation of context the neural representation of environment and this makes sense if you think about how we try to remember things right if you try to remember something and you know it's an impressionist painter or you know it's within a category but you're not quite there you kind of take a tour of categorical ways of thinking and categorical learning and categorical objects in the world to try to get at how that that one fact that one bit of information that you're trying to remember so it's not that individual memories are stored in neurons it's not that they're stored in the kind of the generation of synapses it's not that they are stored in the entirely just the plasticity of single synapses that it seems that we can get at and explain a lot of these types of memory by understanding that memory is kind of one aspect of a formation of these kind of neural networks and that if we have a hundred billion neurons we can imagine elaborate and complex ways of designing these things so here we go one more time many very different things happen when we remember write everything down from the synaptic plasticity all the way up to this impressionism categorical way of thinking and remembering about things and what is again interesting here is that you can imagine what what we've learned about polymorphisms right genetic individual individuality and variation that certain people can have different stress responses you know the person next to you can have a different response to stress than the other person one person will be more afraid of public speaking than the other person one person will respond a certain way based on prenatal postnatal environment all these different things all these different variations these polymorphisms that lead to individual and varied behavior and now we can understand that kind of a polymorphism in how much presynaptic glutamate gets released remember glutamate excitatory a a polymorphism in how strongly your postsynaptic receptor responds a polymorphism in the ways in which your kind of neural networks are constructed these types of individual things which each are their own variable in this kind of brain in your brains construct of memory can need two different in individual ways in which we remember some people are just better at remembering than others and what we're trying to get at is from the spectrum of hm can't remember anything pew Stephen Wiltshire who can remember this and where the genetics and the environment kind of impact our individual memory I think that's it so we'll take a five-minute break and I'm going to talk to you guys about the autonomic nervous system so basically autonomic sounds like automatic this is anything that's going to happen automatically in your body not quite the hippocampus fours like hip and drone syndrome like with automatic autonomic so basically like your heart feeding um digesting goosebumps orgasm things that you don't have a control over that's good stuff right this is gonna be your autonomic nervous system okay so first the nervous system remember is split up into the central and the peripheral so our central nervous system is our brain in our spinal cord and our peripheral nervous system is everything else on the periphery and then within that the peripheral nervous system can be split up into the somatic nervous system and the autonomic so we're going over the Ottoman tonic remember that but just to tell you that the somatic that's basically the voluntary nervous system so like if you want to pick up a pen off the ground you you know your brain says okay I want to pick up a pen send the message to my muscle muscles going to pick up the pen it's also your sensory info so when you touch something or smell something information from the periphery going to your central nervous system and autonomic nervous system what we're going to talk about today can be split up into the parasympathetic and sympathetic nervous systems we'll go over all those in detail but right now one last comparison of the voluntary and autonomic so the voluntary nervous system remember voluntary moves muscles autonomic it's involuntary moving organs your heart your digestive system your lungs the voluntary nervous system is actually myelinated so what that means is there's a myelin sheath covering the axon as you can see there and the action potential actually can speed up and go down the axon faster and autonomic nervous systems actually unmyelinated these are just fun facts um so it goes a little bit slower okay the good stuff um autonomic nervous system so we have sympathetic and parasympathetic and like sympathetic is that nervous system where you hear a fight-or-flight so anything exciting arousal alertness emergency like if you have a hippo chasing after you or something definitely sympathetic nervous system if you like somebody and are like talking to them first-time sympathetic nervous system activation you're excited parasympathetic is more of the calm vegetative function so after you have a huge meal or when you want to take a nap anything like that growth repair just like total relaxation state and as you can see they kind of sound like they have opposing functions because they do and they tend to work in opposition so it's kind of like putting your foot on the gas and the brake at the same time you can't really do that because they're opposing when the parasympathetic system is on your sympathetic nervous system is usually off and vice versa so they work together to like keep our body going automatically ah sympathetic nervous system so remember this is like that huge animal whatever your favorite one is chasing after you what do you do right well your heart speeds up it's going to beat faster you're going to breathe more you're in a basal constrict so what that means is you're sending the blood you're you're basically constricting your blood vessels and sending blood more to your lungs and to your muscles so you can run away you're going to inhibit digestion like when you're running away from a hippo if you don't care about digesting this or like the sandwich you has had you're going to sweat your muscles will tense just anything you would think of when you're just like totally freaked out right and the parasympathetic nervous system so yeah I really like these pictures uh I like some the dog and I got super excited and then I found him and I wanted to name him that have thought of it yet so but basically they're resting and digesting right they're just taking it easy like growth repair basically anything you would do when you're not stressed you have time to do now like your immune system can function well you can spend time digesting and urinating high sympathetic nervous system so we're going to look into the neurotransmitters involved in both the symptoms now so like how honored like neurons like what's being communicated and I know that Pat told you glutamates the best but I'm going to like fight that and tell you that norepinephrine is one of the good ones too so basically you release norepinephrine in the target Oren's when you're dealing with the sympathetic nervous system so the hippo coming at you right what you do is you're going to Billy snort for nephron Andy onto the target ordnance and like you can see the organs on the left or the right it affects all those so it's going to your heart it's going to your lungs it's going to your kidney your bladder and it's telling it when it receives norepinephrine those organs know okay my sympathetic nervous system is activated I'm going to like fight-or-flight I'm going to run away right now or I'm going to start like my heart is going to be faster and the one exception is the sympathetic nervous system actually releases epinephrine in the adrenal and this is just a cool exception epinephrine right remember it's one step away from norepinephrine in the biosynthetic pathway so you can make epinephrine from norepinephrine so they're not really that different and also it's epinephrine is also called adrenaline right adrenal jerilyn see the resemblance and this is just like another um diagram again showing you norepinephrine released on the target organ so you think of sympathetic you think of norepinephrine and you can see how it will go and like accelerate the heartbeat stuff like that and just more in detail um if you've taken bio core and I don't know about humble core but definitely bio core you know that it's not that simple you don't need to worry about this but there's actually a an intermediate step where the spinal cord projections actually first go to this ganglion which then goes to the target oran and releases any there but don't worry about that to snow norepinephrine sympathetic okay parasympathetic nervous system so we have another cool neurotransmitter besides glutamate and n E which is accede oh cool lean or ACH and the parasympathetic you see it goes to all the same organs but now when it releases ACH those organs no parasympathetic rest and digest like I have time to you know finish my meal and do everything that I can do when I want to relax and again there is an intermediate step where you really succeed o : first in the target organ that a second neuron goes releases acetylcholine again there's no ACH parasympathetic and if you want more details about it - it's this slide is totally extra details but it you can see like the projections from the spinal cord actually leave from different places in the parasympathetic and the sympathetic nervous system and you can just see at the end acceded : your norepinephrine being released alright so this is a really important slide that slides that stars on it uh even suppose he when he saw my powerpoints like spend a lot of time in that slide so I'm going to okay so we're going to look at exactly what happens when your parasympathetic or sympathetic nervous systems are activated and compare them to in like different organs so the easiest one to start with is your cardiovascular system so your heart right you're running away you're scared or you're meeting someone new for the first time that you like you really like and your sympathetic nervous system turns on your heart's going to be faster remember that so your heart actually has a mild genic rhythm which means it actually has a muscle that is controlling its feeding but what the brain does in the sympathetic and parasympathetic nervous system does is it can change how fast the heart beats so your heart's beating faster your blood pressure will increase when your sympathetic nervous system is on you're in a basal constrict remember send the blood to your muscles so you can run away and all that good stuff paracin decided right opposite slow our heart beat like vasodilation of the vessels Bloods now go into the GI tract for digestion and everything like that um another fun example is the GI tract itself so your got your stomach or small intestine so basically parasympathetic activity when you're resting you have time to digest so what you do is you you stimulate the secretion of the acids and enzymes needed for digestion you move your spa intestine with the contraction called peristalsis um and basically you can go to the bathroom ah and everything that you do while you're relaxing and then so sorry um okay so in the heart and the GI tract you can pretty much see that they're like working in opposition so like when the heart beats up with sympathetic it slows down with parasympathetic GI the opposite case right parasympathetic turns it on speeds up digestion parasympathetic turns it off I'm sorry this is the important slide okay so one place where they actually do work together instead of actually like opposing each other is in the male reproductive system and they work together for you to erect and ejaculate so what happens is in order to have an erection right you have to be stress-free you can't be worrying about your task so some pit which one which one do you think is in charge of erection parasympathetic or sympathetic perfect so parasympathetic activation you get an erection okay now let's say you have an erection now you're like with somebody maybe I don't know what you're doing but whatever is happening like um sorry okay so your heart like all of a sudden you feel your heart beating faster you start sweating a little bit right your sympathetic nervous system is turn it on a little bit now so now we have pair of SIM set we still have our erection but like we also have some sympathetic activity and then more and more sympathetic activity and all of a sudden sympathetic activity completely takes over and what happens you Jacka late right so parasympathetic erection sympathetic ejaculation and it's actually um a cool facts about erectile dysfunction is that about 60% of the cases are due to stress and not actually organic basis in your body right so if you're stressed out all the time your parasympathetic activity won't turn on so you can't have an erection um and also we can explain premature ejaculation if you want to to your friends tonight um you can just be like well let's think about it so I have an erection but I'm going to jackal it too soon so parasympathetic transition to sympathetic transition or the parasympathetic transition to sympathetic happens too quickly your premature ejaculation okay uh and then like health rights immune system when you pull your parasympathetic system is on you can take care of your immune system right you have the time to make the white blood cells but when you're chasing away from like a predator or like a elephant you really don't care about making you white blood cells and this could also explain why it's easier to get sick when you're stressed out your sympathetic is like too much caring about your stressful situation then taking care of your immune system okay I don't know oh my computer doesn't sleep I think that's it okay so again we see there's a balance between the two branches so sympathetic you're chasing running away from a snake when that's on parasympathetics off and vice versa and there's actually a really cute video that I found and you have to click it twice okay um so yeah so the sympathetic nervous system right this like video will tell you everything I just told you it increases heart rate make sure pupils dilate so you can see further run away from the predator you don't have time to digest you don't care about nasal secretions right now you're not going to produce a lie but who cares I'll eat it any liquor inhibits the liver kidneys and gall bladder and stimulates sweating right we're gonna sweat when running away getting scared causes paddle erections so your hair's down when you're nervous makes the lungs dilate you can breathe faster increases muscle strength that'll okay so you can run away as important for orgasm sorry okay parasympathetic opposite so it makes your heart rate go down people's are going to contract you're going to digest um you know you like the nasal secretions now and you're going to stimulate the liver the bladder and kidneys you constrict your lungs right you're going to pay more attention to your digestion is important for sexual arousal remember eruptions okay you can play again later I'm gonna try hi so an important point to make is when we think about sympathetic nervous system we're thinking about arousal emergency fight-or-flight but that doesn't mean it always goes to the organ and it sites it so like yeah in the heart when norepinephrine goes from the sympathetic nervous system to the heart it does excite the heart and make it beat faster but when it goes to the GI tract and inhibits GI tract activity so it's not always excited Tory it's not always inhibitory it depends on the organ same with parasympathetic we think of it as being the like the slower moving one but you know in the GI tract it does excite it in the heart inhibits so what does that mean that means we need two different receptors on Oliver on our organs that respond to norepinephrine or exceed opaline so on the heart for instance and for norepinephrine you'll have an excitatory norepinephrine receptor because it will get excited and will make the heart beat faster but on the GI tract you'll have an inhibitory norepinephrine receptor that will respond to the sympathetic nervous system and slow it down and then for the parasympathetic you'd have an excitatory ACH receptor on your GI tract to speed it up to digest more food and you'll have an inhibitory ACH receptor on the heart to slow it down so to see like you can't always have the same receptor on the same organ or else it wouldn't respond right and this is just showing you again so like the heart there you have your inhibitory ACH receptor just tells your heart slow down excitatory norepinephrine heart speeds up X and then the GI tract you if you like ACH is coming your way it will attach to the excitatory receptor and it digests and you have the inhibitory norepinephrine receptor there too so if sympathetic activity is being stimulated norepinephrine will land there and it will slow down digestion and so like if you've taken bio core if you want to know more so there's actually names for all these forms of receptors that I put there just in case you're extra and interested um but on the heart I think the coolest form is the beta blocker or the coolest fact about it is the beta blocker so the form of the resep sure on the heart that responds to the sympathetic nervous system is actually called a better receptor and what beta blockers do right they block the receptor the beta receptor so this is why better blockers are used for like slowing down heart rate reducing hypertension basically blocking the effects of the sympathetic nervous system and Pat actually just told me it looks good that um the one drug that's like banned from the Olympics are actually better blockers because if you think about it like a huge advantage would be like to be less stressed so they're blocking the receptor on your heart that like responds to stress and like the sympathetic nervous system you can see how it allow you to relax more so it's a fun fact um okay so now we're going to talk about the regulation of the autonomic nervous system so what's happening in the brain that's resulting in norepinephrine or acetylcholine being released and the center of regulation is now the hypothalamus so yeah we need to talk about the hippocampus so this is a different area of the brain the hypothalamus it's going to be very important on Monday as well when Tom and we'll talk about the endocrine system because the hypothalamus directly affects the pituitary gland which is center of their endocrine system so basically the hypothalamus here contains the cell bodies or just like one synapse away from all the cell bodies that project onto the target organs right from the spinal cord to the target organs so basically the hypothalamus will tell the spinal cord to what to project onto the organ okay so an example of this would be like in your heart and this is actually called the barrel reflex and this is just an example of how your hypothalamus is going to help your body maintain status quo so like make sure that your blood pressure's never too high your heart's beating at a normal speed so like let's say you're hemorrhaging cuz I don't know like a hyena just attacked you and guys ah so anyways you're hemorrhaging and you're losing a lot of blood so your blood pressure is going to go way down and you have these like receptors and your blood vessels they're called baroreceptors they'll say okay blood pressure is way too low what do I do they're going to send that info to the hypothalamus remember the hypothalamus Center regulation and the hypothalamus will be in charge of sending that information along to the spinal cord which will then project on to the heart and tell it to beat faster sympathetic nervous system will be activated beat faster increase my blood pressure so that you'll like make up for the loss of blood that you just had okay and the opposite would happen if your blood pressure is getting too high or something maybe the info you sent to your brain and then you can decrease blood pressure through the parasympathetic nervous system okay so reptiles everybody kind of has that hypothalamus control of the yeah yeah oh cuz remember like ones on or off so like actually like which ones normally on I think so you guys know anybody know yeah um hi so what about like mammals right mammals have emotions and we have an emotional regulation like air in our brain that's called a limbic system and we're going to learn a whole lecture just about the limbic system in general but basically has everything to do with emotions behaviors memories all mammalian type things and like so now we see this realm we're not just you know losing all your blood can activate or stimulate the nervous system and like cause a parasympathetic or sympathetic response but now just like seeing someone you hate like can cause the sympathetic response it's very similar to like losing a lot of blood and this is pretty amazing like wildebeest friends if they see their enemies will go they're bought the info will be sent from just the smell of their enemies to the limbic system project onto the hypothalamus spinal cord to the sympathetic nervous system be like I don't like you response kinda sympathetic nervous system wanting to like either fight or flight' right and then in the realm of primates we also have our cortex and what the cortex does is it makes thoughts and memories really important so now instead of just having you know losing a lot of blood like changing how our body functions and now just like not even having a sense like we don't need to have a sense we can just think about a thought and I can go ahead and change the way that every organ in our body functions which is pretty amazing so like when you're thinking about a test for instance you're going to activate your cortex and this will activate your limbic system then your hypothalamus that's known actually as the trying system of the brain is you have the cortex and primates mostly then you have the limbic system mostly million mammals and then you have the hypothalamus right so it's going to go to each one of these labor like like layers of the brain and just thinking about a task and cause a sympathetic response where you will start sweating getting nervous stressed out and it's pretty amazing that just like if you lost a lot of blood in a reptile that's this kind of we can simulate the same response just thinking about something or thinking about something on the other side of the world dying it's just amazing what like primates can do and an interesting example of this and I think we're having a lecture on depression so I don't want to give it all away yet but if you think about it like the symptoms of depression loss of pleasure pain pathways on don't want to have sets aren't in the mood to eat you're exhausted all the time a lot of these symptoms are the same symptoms you would see if your sympathetic nervous system was overly activated and we can see how a cortex having bad thoughts can go and activate that system in the same way links to a depression so high and the last thing I wanted to talk about in terms of the autonomic nervous system was the plasticity of it so we just learn like the plasticity right in neurons and the synapses so the one that can change over time and the autonomic nervous system can actually change over time in terms of how receptive or when it turns on and off and Molecular example of this is if like you're a very stressful person and you're stressing all the time well then you need a lot of norepinephrine right what what do you do if you're stressing all the time you increase the synthesis of the enzyme called tyrosine hydroxylase I believe yes it's up there and basically this is the rate limiting step in making norepinephrine so if you increase more the enzyme increase more than or brunelfran you can sustain the stress response another example cellular example is that we have projections from the sympathetic nervous system to the skin eyes nose like everything that's going on up there and let's say we see something scary we can make those receptors more sensitive to that scary thing so we can say hey it actually smells that enemy like we can make it seem scarier and the sympathetic nervous system can turn on faster so sensitization there's also the opposite end of the spectrum we're like you have bit xu8 to the wrist to things are going on outside so like scary stimuli like if you want to if you see a spider in your room the first time you're probably going to freak out when you're younger and lots of sympathetic activity running away fight or flight you decide to fly because I don't like spiders um but basically after a while second time you see the spider you're like okay this is still scary maybe I'll run away the third time maybe you'll like decides whatever I'm just going to leave it there at this point and you're habituated to it so you've made the thresholds of your leg of your sensory receptors like they don't care as much they don't respond as much and a last example and we're talking about cognitive thought and the cortex and what that can do to change your autonomic nervous system is that is it an example of biofeedback and blood pressure so basically if you have high blood pressure you can go into the doctor's office and you have two options right you can take medicine or you can try biofeedback and what they do is they like tell you to think of a pleasant thought so like think of your favorite vacation or think of your favorite person or just think of the beach in general and what you'll see is that your blood pressure will actually decrease with a certain thought and then the doctor will tell you to think about that thought again your blood pressure will crease and thinking more and more about that thought helping you build your blood pressure decrease what you do is you potentiate remember you make stronger the connection where a cortical thought can go ahead and like activate more some pair of sympathetic tone have less sympathetic tone so we're like potentiating that pathway what why which a thought can cause our blood pressure to decrease which is pretty cool okay so take-home points if you want to just like know what to remember from this know the broad difference between autonomic automatic right and the voluntary nervous system what we talked about at the beginning understand the neurotransmitters involved in each and why you need two types receptors right the inhibitory and excitatory know one or two examples of what the parasympathetic that's what pns by the way means and sympathetic nervous system due to an organ so remember the heart the digestive tract the male reproductive system and then Noah broad overview of how the brain regulates the autonomic nervous system so hypothalamus cortex right and we have the limbic system okay and on Monday we're going over endocrinology and so have a good for more please visit us at stanford.edu